Initiation of antiretroviral therapy at high CD4+ cell counts is associated with positive treatment outcomes

Objective:There is limited research investigating the possible mechanisms of how starting combination antiretroviral therapy (cART) at a higher CD4+ cell count decreases mortality. This study investigated the association between initiating cART with short-term and long-term achievement of viral suppression; emergence of any drug resistance and of an AIDS-defining illness (ADI); long-term treatment adherence; and all-cause mortality. Methods:This retrospective cohort study included 4120 naive patients who initiated cART between 2000 and 2012. Patients were followed until 2013, death or until the last contact date (varied by outcome). The main exposure was the interaction between period of cART initiation (2000–2006 and 2007–2012) and CD4+ cell count at cART initiation (<500 versus ≥500 cells/&mgr;l). We considered both baseline and longitudinal covariates. We fitted different multivariable models using cross-sectional and longitudinal statistical methods, depending on the outcome. Results:Patients who initiated cART with a CD4+ cell count at least 500 cells/&mgr;l in 2007–2012 had an increased likelihood of achieving viral suppression at 9 months and of maintaining an adherence level of at least 95% over time, and the lowest probability of developing any resistance and an ADI during follow-up. These patients were not the ones with the highest likelihood of maintaining viral suppression over time, most likely due to viral load blips experienced during the follow-up. Conclusion:The outcomes in this study likely play an important role in explaining the positive impact of early cART initiation on mortality. These results should alleviate some of the concerns clinicians may have when initiating cART in patients with high CD4+s as recommended by current treatment guidelines.

[1]  E. Daar Faculty of 1000 evaluation for Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2016 Recommendations of the International Antiviral Society-USA Panel. , 2017 .

[2]  S. Walmsley,et al.  Dolutegravir efficacy at 48 weeks in key subgroups of treatment-naive HIV-infected individuals in three randomized trials , 2015, AIDS.

[3]  J. Gallant,et al.  Rationale and evidence for human immunodeficiency virus treatment as prevention at the individual and population levels. , 2014, Infectious disease clinics of North America.

[4]  T. Berheto,et al.  Predictors of Loss to follow-up in Patients Living with HIV/AIDS after Initiation of Antiretroviral Therapy , 2014, North American journal of medical sciences.

[5]  H. Rees,et al.  Addressing the Achilles' heel in the HIV care continuum for the success of a test-and-treat strategy to achieve an AIDS-free generation. , 2014, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[6]  P. Harrigan,et al.  Performance of HIV-1 drug resistance testing at low-level viremia and its ability to predict future virologic outcomes and viral evolution in treatment-naive individuals. , 2014, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[7]  P. Kaleebu,et al.  Enhanced normalisation of CD4/CD8 ratio with early antiretroviral therapy in primary HIV infection , 2014, Journal of the International AIDS Society.

[8]  Jeffrey W. Eaton,et al.  HPTN 071 (PopART): A Cluster-Randomized Trial of the Population Impact of an HIV Combination Prevention Intervention Including Universal Testing and Treatment: Mathematical Model , 2014, PloS one.

[9]  James J. Goedert,et al.  Closing the Gap: Increases in Life Expectancy among Treated HIV-Positive Individuals in the United States and Canada , 2013, PloS one.

[10]  H. Trottier,et al.  Virologic failure following persistent low-level viremia in a cohort of HIV-positive patients: results from 12 years of observation. , 2013, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[11]  J. Gatell,et al.  Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. , 2013, The Lancet. Infectious diseases.

[12]  S. Cole,et al.  A systematic review and meta-regression of temporal trends in adult CD4(+) cell count at presentation to HIV care, 1992-2011. , 2013, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[13]  Anne M Johnson,et al.  Role of HIV Infection Duration and CD4 Cell Level at Initiation of Combination Anti-Retroviral Therapy on Risk of Failure , 2013, PloS one.

[14]  T. Bärnighausen,et al.  Evaluation of the impact of immediate versus WHO recommendations-guided antiretroviral therapy initiation on HIV incidence: the ANRS 12249 TasP (Treatment as Prevention) trial in Hlabisa sub-district, KwaZulu-Natal, South Africa: study protocol for a cluster randomised controlled trial , 2013, Trials.

[15]  Y. Yazdanpanah,et al.  Durable Efficacy and Safety of Raltegravir Versus Efavirenz When Combined With Tenofovir/Emtricitabine in Treatment-Naive HIV-1–Infected Patients: Final 5-Year Results From STARTMRK , 2013, Journal of acquired immune deficiency syndromes.

[16]  E. Nicastri,et al.  Risk of clinical progression among patients with immunological nonresponse despite virological suppression after combination antiretroviral treatment , 2013, AIDS.

[17]  F. Behets,et al.  Initiating antiretroviral therapy when presenting with higher CD4 cell counts results in reduced loss to follow-up in a resource-limited setting , 2013, AIDS.

[18]  B. Branson,et al.  Use of HIV Case Surveillance System to Design and Evaluate Site-Randomized Interventions in an HIV Prevention Study: HPTN 065 , 2012, The open AIDS journal.

[19]  B. Yip,et al.  Technical and Regulatory Shortcomings of the TaqMan Version 1 HIV Viral Load Assay , 2012, PloS one.

[20]  P. Tebas,et al.  Efficacy and safety of rilpivirine in treatment-naive, HIV-1-infected patients with hepatitis B virus/hepatitis C virus coinfection enrolled in the Phase III randomized, double-blind ECHO and THRIVE trials. , 2012, The Journal of antimicrobial chemotherapy.

[21]  Michael Rayment,et al.  Prevention of HIV-1 infection with early antiretroviral therapy , 2012, Journal of Family Planning and Reproductive Health Care.

[22]  B. Uzochukwu,et al.  Retention and loss to follow-up in antiretroviral treatment programmes in southeast Nigeria , 2012, Pathogens and global health.

[23]  D. Bangsberg,et al.  Antiretroviral therapy refusal among newly diagnosed HIV-infected adults , 2011, AIDS.

[24]  A. Lazzarin,et al.  Long-term treatment with raltegravir or efavirenz combined with tenofovir/emtricitabine for treatment-naive human immunodeficiency virus-1-infected patients: 156-week results from STARTMRK. , 2011, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[25]  D. Katzenstein,et al.  Abacavir/lamivudine versus tenofovir DF/emtricitabine as part of combination regimens for initial treatment of HIV: final results. , 2011, The Journal of infectious diseases.

[26]  S. Cole,et al.  Timing of HAART initiation and clinical outcomes in human immunodeficiency virus type 1 seroconverters. , 2011, Archives of internal medicine.

[27]  A. Lazzarin,et al.  Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active-controlled trial , 2011, The Lancet.

[28]  James M Robins,et al.  When to Initiate Combined Antiretroviral Therapy to Reduce Mortality and AIDS-Defining Illness in HIV-Infected Persons in Developed Countries , 2011, Annals of Internal Medicine.

[29]  P. Harrigan,et al.  Risk of Viral Failure Declines With Duration of Suppression on Highly Active Antiretroviral Therapy Irrespective of Adherence Level , 2010, Journal of acquired immune deficiency syndromes.

[30]  N. Ford,et al.  Treatment Interruption in a Primary Care Antiretroviral Therapy Program in South Africa: Cohort Analysis of Trends and Risk Factors , 2010, Journal of acquired immune deficiency syndromes.

[31]  S. Lauwers,et al.  Correction of Underquantification of Human Immunodeficiency Virus Type 1 Load with the Second Version of the Roche Cobas AmpliPrep/Cobas TaqMan Assay , 2010, Journal of Clinical Microbiology.

[32]  Michael J Silverberg,et al.  Effect of early versus deferred antiretroviral therapy for HIV on survival. , 2009, The New England journal of medicine.

[33]  C. Armon,et al.  Initiation of HAART at Higher CD4 Cell Counts Is Associated With a Lower Frequency of Antiretroviral Drug Resistance Mutations at Virologic Failure , 2009, Journal of acquired immune deficiency syndromes.

[34]  Stephen R Cole,et al.  Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies , 2009, The Lancet.

[35]  B. Yip,et al.  The Combined Effect of Modern Highly Active Antiretroviral Therapy Regimens and Adherence on Mortality Over Time , 2009, Journal of acquired immune deficiency syndromes.

[36]  Christopher Dye,et al.  Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model , 2009, The Lancet.

[37]  D. Richman,et al.  2022 update of the drug resistance mutations in HIV-1. , 2022, Topics in antiviral medicine.

[38]  A. Phillips,et al.  Determinants of Virological Failure after Successful Viral Load Suppression in First-Line Highly Active Antiretroviral Therapy , 2008, Antiviral therapy.

[39]  A. Levy,et al.  Expanded access to highly active antiretroviral therapy: a potentially powerful strategy to curb the growth of the HIV epidemic. , 2008, The Journal of infectious diseases.

[40]  J. Gatell,et al.  Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study. , 2008, The Journal of infectious diseases.

[41]  B. Gazzard,et al.  Risk of extensive virological failure to the three original antiretroviral drug classes over long-term follow-up from the start of therapy in patients with HIV infection: an observational cohort study , 2007, The Lancet.

[42]  Wolfram Schumacher,et al.  Fully automated quantification of human immunodeficiency virus (HIV) type 1 RNA in human plasma by the COBAS AmpliPrep/COBAS TaqMan system. , 2007, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[43]  Evan Wood,et al.  The case for expanding access to highly active antiretroviral therapy to curb the growth of the HIV epidemic , 2006, The Lancet.

[44]  S. Mallal,et al.  Clinical and immunogenetic correlates of abacavir hypersensitivity , 2005, AIDS.

[45]  B. Gazzard,et al.  Long term probability of detection of HIV-1 drug resistance after starting antiretroviral therapy in routine clinical practice , 2005, AIDS.

[46]  J. Ware,et al.  Applied Longitudinal Analysis , 2004 .

[47]  D. Brambilla,et al.  Ultrasensitive Reverse Transcription-PCR Assay for Quantitation of Human Immunodeficiency Virus Type 1 RNA in Plasma , 1998, Journal of Clinical Microbiology.

[48]  P. Kissinger,et al.  Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. , 1998, The New England journal of medicine.

[49]  G. Satten,et al.  Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. , 1998, The New England journal of medicine.

[50]  S. Hammer,et al.  Antiretroviral therapy for HIV infection in 1996. Recommendations of an international panel. International AIDS Society-USA. , 1996, JAMA.

[51]  Douglas D. Richman,et al.  Antiretroviral therapy for HIV infection in 1996 : Recommendations of an international panel , 1996 .

[52]  D. Richman,et al.  Influence of the timing of antiretroviral therapy on the potential for normalization of immune status in human immunodeficiency virus 1-infected individuals. , 2015, JAMA internal medicine.

[53]  Jennifer F Hoy,et al.  Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel. , 2014, JAMA.

[54]  Douglas D. Richman,et al.  Antiretroviral Treatment of Adult HIV Infection , 2008 .

[55]  B. Rewari,et al.  Antiretroviral Therapy for HIV Infection , 2007 .